US 12,094,586 B2
Materials and methods relating to dosage regimen design
Hans Peter Grimm, Basel (CH); Benjamin Ribba, Basel (CH); and Volker Teichgräaeber, Bottmingen (CH)
Assigned to HOFFMANN-LA ROCHE INC., Little Falls, NJ (US)
Filed by Hoffmann-La Roche Inc., Little Falls, NJ (US)
Filed on Nov. 20, 2018, as Appl. No. 16/196,883.
Application 16/196,883 is a continuation of application No. PCT/EP2017/062302, filed on May 22, 2017.
Claims priority of application No. 16171263 (EP), filed on May 25, 2016.
Prior Publication US 2019/0361018 A1, Nov. 28, 2019
Int. Cl. G16H 20/10 (2018.01); G16H 50/50 (2018.01)
CPC G16H 20/10 (2018.01) [G16H 50/50 (2018.01)] 18 Claims
OG exemplary drawing
 
1. A method for treating an individual in need thereof with an effective dose of a therapeutic agent comprising
a) requesting a test providing results of an analysis to determine an effective amount of said therapeutic agent for the individual; and
b) administering said therapeutic agent to the individual at the determined effective amount;
wherein said test comprises
a) simulating a model, using data obtained from the individual at one or more time points following a first or previous dose administration of the therapeutic agent; wherein the data includes (i) PK data relating to the amount of unbound therapeutic agent; (ii) PD data relating to immune cells expressing IL2 receptor; and (iii) imaging data relating to the amount of therapeutic agent that is taken up by the therapeutic target tissue,
wherein the model is:

OG Complex Work Unit Math
wherein:
[Ab]free is the concentration of unbound therapeutic agent in plasma,
[IL2R]free is the concentration of unbound immune cells expressing IL2 receptor in blood, which is given by kin/kout if the data does not include the PD data, or it is obtained from the PD data if the data includes the PD data,
[Complex] is the concentration of complex between the therapeutic agent and immune cells expressing IL-2 receptor (IL2R+ cells),
[Ab]totalT is the concentration of therapeutic agent in the target tissue,
kclear is a constant rate of elimination of therapeutic agent from plasma and has a value between 0.02 and 0.04 hour-1;
kon is an association rate of complex between the therapeutic agent and immune cells expressing IL-2 receptor and has a value between 0.26 and 4.5 μM−1h−1,
koff is a dissociation rate of complex between the therapeutic agent and immune cells expressing IL-2 receptor and has a value between 0.0035 and 0.02 h−1,
kin is a constant influx rate of IL2R+ cells in plasma and has a value between 0.0006 and 0.0144 μMh−1;
kout is a natural decay rate of IL2R+ cells in plasma and has a value between 0.0018 and 0.069 h−1,
kint is the internalization rate of the therapeutic agent and has a value between 0.0066 and 0.023 h−1; and
η is a constant rate of expansion of IL2R+ cells in plasma as a result of the binding (internalization) of the therapeutic agent and has a value between 1.02 and 3.31;
P is the permeability across capillary vessels;
RCap is the capillary radius;
RKgrogh is the radius of the Krogh cylinder;
Kd is the dissociation constant;
[Ag] is the concentration of antigen in the tissue;
ε is the volume fraction; and
ke is the constant rate of drug internalization and degradation from the target tissue;
b) determining an effective dose for the individual based on the increase in therapeutic agent required to compensate for reduction in free therapeutic agent, wherein the optimal dosing regimen provides the best target tissue uptake compared to other simulated dosing regimens;
wherein the therapeutic agent is a compound which is capable of targeting IL2R.